The emergence of potential reduced-exposure tobacco and cigarette-like products and the reduction of smoking as a treatment approach, have recently been forcing the debate and discussion about the science that is necessary to inform policies, regulation, and programs. To deal effectively with the issues evolving around tobacco harm reduction, a comprehensive and strategic research agenda must be forged, and a multi-disciplinary, collaborative approach must be taken. The goal of this article is to describe research challenges and issues related to tobacco exposure and harm reduction. Scientists from multiple disciplines and individuals from government agencies, nonprofit organizations, and tobacco control advocacy groups as well as the pharmaceutical and tobacco industries attended a two-day meeting that focused on addressing the current knowledge regarding tobacco harm reduction, identifying gaps in knowledge, and recommending research directions. Workgroups, comprising a subset of attendees, met after the conference to synthesize, discuss, and prioritize the important research frontiers. The resulting document provides guidance for scientists, grant funding agencies, industry and policy makers by identifying areas in which to invest research effort and funds to develop a science base to ensure the future health of this nation and world.